The present invention relates to novel substituted derivatives of 3-amino-2-hydroxypropionic acid useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment as well as the use of these agents as diagnostic tools. More particularly, the novel compounds of the present invention inhibit the enzyme renin thus controlling hypertension, hyperaldosteronism and congestive heart failure in mammals.
Renin is a natural enzyme which is released into the blood stream from the kidney. It cleaves its natural substrate, angiotensinogen, releasing a decapeptide, angiotensin I. This in turn is cleaved by converting enzyme in the lung, kidney and other tissues to an octapeptide, angiotensin II. Angiotensin II raises blood pressure both directly by causing arteriolar constriction and indirectly by stimulating release of the sodium-retaining hormone aldosterone from the adrenal gland causing a rise in extracellular fluid volume. Inhibitors of renin have been sought as agents for control of hypertension and hyperaldosteronism.
U.S. Pat. No. 4,656,269 discloses certain renin-inhibiting peptides of the formula ##STR1## wherein R.sup.1 represents a monoalkylamino group having one to three carbon atoms, a dialkylamino group having two to six carbon atoms, or ##STR2## in which Y represents a chemical bond, an oxygen atom or a methylene group, His represents an L-histidyl group, n represents zero or 1, X represents an oxygen atom or --NH--, R.sup.2 represents a straight or branched alkyl group having one to seven carbon atoms.
European Patent Application 0.216,539 discloses reinin-inhibiting peptides of the formula ##STR3## wherein R.sup.1 represents ##STR4## in which R.sup.1 represents a lower alkyl group, X represents an amino acid residual group selected from glycine, alanine, .beta.-alanine, valine, leucine, phenylalanine, tryptophane and serine, n is zero or 1, Y represents --O--, or --NH--, and R.sup.2 represents a straight- or branched-chain alkyl group having one to seven carbon atoms. European Patent Application 0,200,406 disclosed a renin-inhibiting peptide of the formula ##STR5##